Oncogenic H-ras stimulates tumor angiogenesis by two distinct pathways

Oncogenic H-ras stimulates tumor angiogenesis by two distinct pathways

^*Department of Dermatology, Harvard Medical School, ^†Department of Surgery, Children’s Hospital, Harvard Medical School, and Departments of ^§Surgery and ^‡‡Cell Biology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115; ^¶Division of Hematologic Malignancies, Dana–Farber Cancer Institute, Boston, MA 02115; ^‖Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461; and ^**Department of Dermatology, Boston University School of Medicine, 80 East Albany Street, Boston, MA 02138

Abstract

The switch from a quiescent tumor to an invasive tumor is accompanied by the acquisition of angiogenic properties. This phenotypic change likely requires a change in the balance of angiogenic stimulators and angiogenic inhibitors. The nature of the angiogenic switch is not known. Here, we show that introduction of activated H-ras into immortalized endothelial cells is capable of activating the angiogenic switch. Angiogenic switching is accompanied by up-regulation of vascular endothelial growth factor and matrix metalloproteinase (MMP) bioactivity and down-regulation of tissue inhibitor of MMP. Furthermore, we show that inhibition of phosphatidylinositol-3-kinase leads to partial inhibition of tumor angiogenesis, thus demonstrating that activated H-ras activates tumor angiogenesis through two distinct pathways. Finally, we show evidence for two forms of tumor dormancy.

Footnotes

↵ ‡ To whom reprint requests should be addressed.
Judah Folkman
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Abbreviations: SV40, simian virus 40; VEGF, vascular endothelial growth factor; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of MMP; diI-Ac-LDL, 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocyanine perchlorate conjugated to acetylated low density lipoprotein.